In 2004 the National Institutes of Health awarded Virginia Commonwealth University (VCU) an NCRR shared instrumentation grant to purchase a X-ray diffraction equipment. The instrument is housed at the Institute for Structural Biology, Drug Discovery and Development (ISBDDD) and is currently used by 24 investigators from the ISBDDD, the departments of Medicinal Chemistry, Chemistry, Internal Medicine, Biochemistry, Pediatrics, Microbiology, Pharmacology and Toxicology, Physiology and Biophysics, and the nearby University of Richmond. The investigators come from diverse research programs: cancer, infectious diseases, thrombosis/hemostasis, gene regulation, drug abuse and addiction, hemoglobinopathies, cardiovascular disease, systems biology, protein function and regulation, etc. Structure-based drug discovery is a major focus and has resulted in several preclinical and clinical drugs over the years. For example, Aes103 is being studied in phase II clinical trials for the treatment of sickle cell disease. Another compound, RSR-13 was investigated for several hypoxic-related diseases and emerged as a candidate for clinical applications, particularly as a radiation enhancer in the radiotherapy of hypoxic tumors. The current Rigaku X-ray diffraction instrument has not been manufactured since 2004, and is becoming very expensive to maintain. Moreover, service and replacement parts for the components are discontinued, and Rigaku has declined to offer any service contract. The age of the instrument has led to significant increase in down time, impacting the drug discovery program, which requires sustained access to in-house data collection integrated with rapid screening protocols of compounds as they become available. There is a need for reliable and enhanced in-house data collection capabilities for uninterrupted support of the investigators and their research programs. VCU is requesting funds from the NIH Shared Instrumentation Grant Program (S10) for the purchase of an X-ray diffraction system that includes the MicroMax-007HF generator, VariMax-HF optics, Pilatus 200K detector, AFC11 goniometer and Oxford cryostream 800. This diffraction system will significantly increase our ability to rapidly and routinely screen and/or collect full datasets to analyze for compound binding sites as well as aid in the optimization and prioritization of research samples to be forwarded for synchrotron data collection. The upgrade will improve the efficiency with which our many structure-related projects are prosecuted and allow us to undertake wide-ranging compound screening in parallel with concurrent major investments in compound libraries and screening infrastructure. It will have direct and indirect effects on the research of a large number of investigators and their collaborators and on the overall research mission of our institution. The proposed instrumentation will significantly advance current NIH-funded research projects and expand the community of users.